lesson 7.1 inborn errors of metabolism

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    Metabolic Diseases

    Inborn Errors Of Metabolism (IEM)

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    A primer on metabolic disease in the neonate...

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    What is a metabolic disease?

    Inborn errors of metabolism

    inborn error : an inherited (i.e. genetic) disorder

    metabolism : chemical or physical changes undergone by

    substances in a biological system

    any disease originating in our chemical individuality

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    What is a metabolic disease?

    Garrods hypothesis

    product deficiency

    substrate excess

    toxic metabolite

    A

    D

    B C

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    What is a metabolic disease?

    Small molecule disease

    Carbohydrate

    Protein

    Lipid

    Nucleic Acids

    Organelle disease

    Lysosomes

    Mitochondria

    Peroxisomes

    Cytoplasm

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    How do metabolic diseases present in the neonate

    ?? Acute life threatening illness

    encephalopathy - lethargy, irritability, coma

    vomiting

    respiratory distress

    Seizures, Hypertonia

    Hepatomegaly (enlarged liver) Hepatic dysfunction / jaundice

    Odour, Dysmorphism, FTT (failure to thrive), Hiccoughs

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    How do you recognize a metabolic disorder ??

    Index of suspicion

    eg with any full-term infant who has no antecedent maternal fever or

    PROM (premature rupture of the membranes) and who is sick enough towarrant a blood culture or LP, one should proceed with a few simple lab

    tests.

    Simple laboratory tests

    Glucose, Electrolytes, Gas, Ketones, BUN (blood urea nitrogen),

    Creatinine

    Lactate, Ammonia, Bilirubin, LFT

    Amino acids, Organic acids, Reducing subst.

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    Index of suspicion

    Family History

    Most IEMs are recessive - a negative family history is not

    reassuring!

    CONSANGUINITY, ethnicity, inbreeding

    neonatal deaths, fetal losses

    maternal family history

    males - X-linked disorders

    all - mitochondrial DNA is maternally inherited

    A positive family history may be helpful!

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    Index of suspicion

    History

    CAN YOU EXPLAIN THE SYMPTOMS?

    Timing of onset of symptoms

    after feeds were started?

    Response to therapies

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    Index of suspicion

    Physical examination

    Generaldysmorphisms (abnormality in shape or size), ODOUR

    H&N - cataracts, retinitis pigmentosa

    CNS - tone, seizures, tense fontanelle

    Resp - Kussmauls, tachypnea

    CVS - myocardial dysfunction

    Abdo - HEPATOMEGALY

    Skin - jaundice

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    Index of suspicion

    Laboratory

    ANION GAP METABOLIC ACIDOSIS

    Normal anion gap metabolic acidosis

    Respiratory alkalosis

    Low BUN relative to creatinine

    Hypoglycemia

    especially with hepatomegaly

    non-ketotic

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    A parting thought ...

    Metabolic diseases are individually rare, but as a group are not

    uncommon.

    There presentations in the neonate are often non-specific at the

    outset.

    Many are treatable.

    The most difficult step in diagnosis is considering the possibility!

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    INBORN ERRORS OF METABOLISM

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    Inborn Errors of Metabolism

    An inherited enzyme deficiency leading to the disruption of normal

    bodily metabolism

    Accumulation of a toxic substrate (compound acted upon by an

    enzyme in a chemical reaction)

    Impaired formation of a product normally produced by the

    deficient enzyme

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    Three Types

    Type 1: Silent Disorders

    Type 2: Acute Metabolic Crises

    Type 3: Neurological Deterioration

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    Type 1: Silent Disorders

    Do not manifest life-threatening crises

    Untreated could lead to brain damage and developmental

    disabilities

    Example: PKU (Phenylketonuria)

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    PKU

    Error of amino acids metabolism

    No acute clinical symptoms

    Untreated leads to mental retardation

    Associated complications: behavior disorders, cataracts, skin

    disorders, and movement disorders

    First newborn screening test was developed in 1959

    Treatment: phenylalaine restricted diet (specialized formulas

    available)

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    Type 2: Acute Metabolic Crisis

    Life threatening in infancy

    Children are protected in utero by maternal circulation which

    provide missing product or remove toxic substance

    Example OTC (Urea Cycle Disorders)

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    OTC

    Appear to be unaffected at birth

    In a few days develop vomiting, respiratory distress, lethargy, and

    may slip into coma.

    Symptoms mimic other illnesses

    Untreated results in death

    Treated can result in severe developmental disabilities

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    Type 3: Progressive Neurological Deterioration

    Examples: Tay Sachs disease

    Gaucher disease

    Metachromatic leukodystrophy

    DNA analysis show: mutations

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    Mutations

    Nonfunctioning enzyme results:

    Early Childhood - progressive loss of motor and cognitive skills

    Pre-Schoolnon responsive state

    Adolescence - death

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    Other Mutations

    Partial Dysfunctioning Enzymes

    -Life Threatening Metabolic Crisis

    -ADH

    -LD

    -MR

    Mutations are detected by Newborn Screening and Diagnostic

    Testing

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    Treatment

    Dietary Restriction

    Supplement deficient product

    Stimulate alternate pathway

    Supply vitamin co-factor

    Organ transplantation

    Enzyme replacement therapy

    Gene Therapy

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    Children in School

    Life long treatment

    At risk for ADHD

    LD

    MR

    Awareness of diet restrictions

    Accommodations

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    Inborn errors of metabolism

    Definition:

    Inborn errors of metabolism occur from a group of rare genetic

    disorders in which the body cannot metabolize food components

    normally. These disorders are usually caused by defects in the enzymes

    involved in the biochemical pathways that break down food components.

    Alternative Names:

    Galactosemia - nutritional considerations; Fructose intolerance -

    nutritional considerations; Maple sugar urine disease (MSUD) - nutritional

    considerations; Phenylketonuria (PKU) - nutritional considerations;

    Branched chain ketoaciduria - nutritional considerations

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    Background:

    Inborn errors of metabolism (IEMs) individually are rare but

    collectively are common. Presentation can occur at any time, even in

    adulthood.

    Diagnosis does not require extensive knowledge of biochemical

    pathways or individual metabolic diseases.

    An understanding of the broad clinical manifestations of IEMs

    provides the basis for knowing when to consider the diagnosis.

    Most important in making the diagnosis is a high index of suspicion.

    Successful emergency treatment depends on prompt institution of

    therapy aimed at metabolic stabilization.

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    A geneticallydetermined

    biochemicaldisorderin which aspecific enzymedefectproduces a

    metabolic blockthat may have

    pathologicconsequences at birth

    (e.g., phenylketonuria) or in later life

    (e.g., diabetes mellitus); called also

    enzymopathyand genetotrophic

    disease.

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